Cytoskeleton-associated protein 5 is a microtubule-associated protein that in humans is encoded by the CKAP5 gene (Nagase et al. DNA Res. 2: 37-43; Charrasse et al. Eur J Biochem 234: 406-13; “Entrez Gene: CKAP5 cytoskeleton associated protein 5”). CKAP5 is also known as ch-TOG, and the Xenopus CKAP5 homolog is XMAP215 (Cassimeris and Morabito. Molecular Biology of the Cell 15: 1580-1590).
The CKAP5 protein plays at least two distinct roles in spindle formation: it protects kinetochore microtubules from depolymerization by MCAK (KIF2C), while CKAP5 protein also plays an essential role in centrosomal microtubule assembly, a function independent of MCAK activity (Barr and Gergely. Molecular and Cellular Biology 28: 7199-7211). It has also been shown to interact with TACC1, which is a candidate breast cancer gene (Conte et al. Oncogene 22: 8102-16; Lauffart et al. Biochem. J. 363: 195-200; “Entrez Gene: TACC1 transforming, acidic coiled-coil containing protein 1”).
Over-expression of CKAP5 has been observed to occur in certain human hepatomas and colonic tumors (Charrasse et al. Eur J Biochem 234: 406-13), and a recent report has proposed CKAP5, as well as additional 20S proteasome subunits MCL1, RRM1 and USP8, to be a molecular vulnerability in human multiple myeloma cells (Tiedemann et al., Cancer Res. 72: 757-68).
Double-stranded RNA (dsRNA) agents possessing strand lengths of 25 to 35 nucleotides have been described as effective inhibitors of target gene expression in mammalian cells (Rossi et al., U.S. Patent Application Nos. 2005/0244858 and US 2005/0277610). dsRNA agents of such length are believed to be processed by the Dicer enzyme of the RNA interference (RNAi) pathway, leading such agents to be termed “Dicer substrate siRNA” (“DsiRNA”) agents. Additional modified structures of DsiRNA agents were previously described (Rossi et al., U.S. Patent Application No. 2007/0265220).
Provided herein are improved dsRNA agents that target CKAP5. In particular, DsiRNAs targeting CKAP5 have been specifically exemplified.